The current data in the literature provide conflicting results on the association of human Toll-like receptor 4 (TLR4) single nucleotide polymorphisms (SNP) and a variety of diseases, including sepsis, meningococcal disease, cerebral malaria, Crohn's disease, ulcerative colitis, respiratory syncytial virus, atherosclerosis, rheumatoid arthritis, malignant melanoma, and metabolic syndrome. Analysis of the role of human TLR4 SNPs in these diverse diseases has been hampered by the lack of a suitable animal model. We have recently developed a new transgenic mouse model that encodes human rather than mouse TLR4 as well as its coreceptor MD-2. This new transgenic line displays more human-like responses to Gram-negative bacterial infections than conventional mice. In this R21 grant application, we propose to extend our studies to newly generated lines expressing the most common human TLR4 variants, namely TLR4D299G and TLR4D299G+T399I. Results obtained here will determine whether these novel TLR4 SNP mice could be of benefit for the study of the large range of infectious and non-infectious diseases where TLR4 SNP associations have been described.